Fundus Autofluorescence in Choroideremia
Agnes B. Renner
Choroideremia (CHM) is a progressive retinal dystrophy with an X-linked mode of inheritance (1, 2, 3) caused by mutations in the CHM gene (4). The name “choroideremia” means an absence (eremia) of the choroid and points out the typical findings in advanced stages of the disease: a complete atrophy of the choroid and visible bare sclera. CHM is characterized by a progressive degeneration of the photoreceptors and retinal pigment epithelium (RPE), followed by a degeneration of the choroid (5). Full-field electroretinogram (ERG) is reduced early on in the disease, showing a rod-cone dysfunction, and with disease progression the ERG becomes nonrecordable (6). Fundus changes are visible during the first decade of life, with mottled RPE alterations in the periphery being the first manifestations of the disease. Subsequently, areas of RPE and choroid atrophy develop in the far periphery and midperiphery. The atrophic lesions increase in size and become confluent, spreading toward the center over the years; however, the macula remains spared for decades of life. Finally, bare sclera is seen throughout the fundus. Nyctalopia is one of the first symptoms in CHM patients. Visual field defects develop in the midperiphery, followed by progression to concentric visual field loss, color vision defects, photophobia, and loss of visual acuity.
Because of the X-linked inheritance, only males are affected. Female carriers who manifest CHM are very rare (2,5,7, 8, 9, 10). Normally, all female carriers show patchy fundus changes, including various grades of mottled RPE alterations, RPE stippling, or spotty pigment atrophy in the periphery. Lyonization, i.e., a random X-inactivation, explains the various phenotypes observed in carriers of the disease (7). The full-field ERG is mostly normal in carriers of CHM.
In addition to a complete eye examination, important diagnostic tools include detailed case and family histories, tests of color vision and visual field, recording of full-field ERG, and fundus autofluorescence (AF). Family members should be examined and, in suspected CHM, a genetic analysis of the CHMgene should be provided. To date, no treatment for CHM is available.
The gene underlying CHM was first described in 1990 (4) and encodes Rab escort protein 1 (REP-1). More than 70 CHM gene mutations have been revealed so far (for details, see http.//www.retina-international.org/sci-news/repmut.htm). All CHM mutations lead to complete loss of the gene product REP-1. Of interest, the gene is ubiquitously expressed; however, mutations affect only the eye (11). This phenomenon is currently explained by a specific gene substrate in the retina and choroid: Rab27a (12). REP-1 is necessary for transferring geranylgeranyl groups to Rab proteins, which are small GTP-binding proteins (4,13,14). Rab proteins are involved in functions such as protein trafficking, endocytosis, intracellular vesicle transportation, and signal transduction (15). For a detailed overview of REP-1 functions, see Preising et al. (16).
CHM gene expression has been shown in rods and RPE cells (5), indicating the origin of the disease in rods and/or RPE cells. Therefore, the degeneration of the cones and choroid seems to be secondary to the demise of rods and RPE. Only a few histopathologic studies of CHM have been published, and those dealt mainly with the eyes of female carriers (5,17, 18, 19); the data regarding affected males are scarce (20). These studies showed patchy degeneration of the retina in female carriers, with mixed areas of normal photoreceptors, photoreceptors that had lost their outer segments, and areas of loss of the entire photoreceptor cells. In addition, RPE changes were found, including abnormal RPE cells with irregularities in thickness, various amounts of melanin and lipofuscin granules with some clumping of melanin granules, and areas with focal RPE hypertrophy or thinning (5). The choriocapillaris was normal except in areas with severe retinal degeneration (5).